Two cases of progressive multifocal leukoencephalopathy (PML) in individuals taking either fumaric acid or a compound of fumaric acid esters were reported in The New England Journal of Medicine (N Engl J Med 2013;368;17:1657-1660) on April 25, 2013. PML is a potentially fatal brain infection with the JC virus (JCV), in people with weakened immune systems. Both of these reports were from Europe in individuals receiving long-term treatment for psoriasis (a chronic skin problem that causes skin cells to grow too quickly, resulting in thick, white, silvery, or red patches of skin [WebMD]).

Tecfidera (dimethyl fumarate) was approved by the Food and Drug Administration (FDA) in March 2013 for the treatment of relapsing forms of multiple sclerosis (MS). In a response that also appeared in The New England Journal of Medicine, Biogen Idec, the makers of Tecfidera, point out that the two medicines listed above (fumaric acid and a compound of fumaric acid esters) only share one of their multiple ingredients with Tecfidera, whose only active ingredient is dimethyl fumarate.

In the first report, a 74-year-old man from Germany had been receiving fumaric acid (brand name, “Fumaderm”) for three years (2007 through 2010), taking two doses of dimethyl fumarate and monoethyl fumarate twice daily. Among other medications, he had also been given topical steroids and methotrexate (a drug that suppresses the immune system) prior to starting Fumaderm – a drug licensed in Germany for the treatment of psoriasis.

One year after starting fumaric acid treatment, the German patient was diagnosed with lymphocytopenia, a disorder in which your blood doesn’t have enough white blood cells called lymphocytes [National Institutes of Health]. White blood cells are part of the immune system and fight infection and disease. This condition increases the risk of developing PML. Although the manufacturer recommended that the patient discontinue the drug, he remained on the medication for two more years, when a diagnosis of PML was made (in August 2010).

The second report was a 42-year-old woman from the Netherlands. Since 2007, she had been taking fumaric acid esters (brand name Psorinovo), made in a compounding pharmacy and consisting of dimethyl fumarate as well as copper gluconate, to treat psoriasis. The copper gluconate was used as an additive until 2010. She apparently experienced lymphocytopenia for five years prior to being diagnosed with PML in 2012.

In the response from Biogen, they note two additional reports of PML in patients with psoriasis treated with Fumaderm. These patients also had various factors that could contribute to the development of PML (such as certain health conditions and prior use of immunosuppressant medications). All together, this is a total of four patients who have been treated with fumarates, three with Fumaderm and one with the compounded fumaric acid esters. Fumaderm is widely prescribed for moderate-to-severe plaque psoriasis, and its safety has been assessed in 19 years of post-marketing surveillance and 180,000 patient years of experience. Compounded fumaric acid esters, however, are not regulated and carry many unknowns, such as the exact composition, quality, and safety.

Fumaderm can cause decreased levels of lymphocytes, but lymphocytopenia is less frequent, occurring in 3 percent of patients. Severe lymphocytopenia increases one’s risk of developing PML, and diagnosing this condition early through the periodic monitoring of lymphocytes, can help to protect patients from developing PML.

For individuals with MS who are or will be taking Tecfidera, the FDA recommends that patients be given a complete blood count prior to starting Tecfidera, and annually thereafter while still on the treatment, to monitor their ability to fight infection. Biogen notes that more than 2,600 MS patients have been treated with Tecfidera for periods of up to four years or more. While lymphocyte counts drop by 30 percent on average, risks of serious or opportunistic infections do not appear to be increased, and no cases of PML have been reported.

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Last Update: Wednesday, August 16, 2017

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